Autoinflammatory diseases Flashcards
What leads to the production of inflammatory cytokines?
Infection
Tissue damage
Environmental stress
What differentiates autoimmune from autoinflammatory conditions?
They lie on opposite ends of the same spectrum
Result due to opposite mechanisms
What is overactive in autoinflammatory conditions?
The innate immune system
What is overactive in autoimmune conditions?
The adaptive immune system
What are the different classes of autoinflammatory and autoimmune conditions?
Polygenic
Monogenic
What is a polygenic condition?
Many genes are responsible for the pathology
What is a monogenic condition?
One gene is responsible for the pathology
Examples of rare monogenic autoinflammatory diseases
CAPS
FMF
TRAPS
PAPA
Examples of polygenic autoinflammatory diseases
Still’s
Chron’s
Ulcerative colitis
Examples of mixed pattern diseases
Reactive psoriasis arthritis
Ankylosing spondylitis
Examples of classic polygenic autoimmune diseases
Rheumatoid arthritis
SLE
Type 1 diabetes
Sjorgen’s syndrome
What is a central mediator of symptoms and signs in autoinflammatory syndromes?
IL-1b
What is the death domain superfamily?
Member of the innate immune system
Play pivotal roles in apoptosis and inflammation
Group of highly conserved and closely related proteins
How many death domains are there in the death domain superfamily?
39
How many death effector domains are there in the death domain superfamily?
8
How many caspase recruitment domains are there in the death domain superfamily?
33
How many pyrin domains are there in the death domain superfamily?
22
Describe the shape of death domains
6 a-helices arranged in antiparallel bundle
Homotypic protein protein interactions
No cross interactions between families
What are the characteristics of autoinflammatory conditions?
No class II HLA-association
No gender predisposition
No auto-antibodies
No antigen-specific T cells
How have autoinflammatory diseases been beneficial to the scientific community?
Allowed us to understand the mechanisms regulating inflammation
Give an example of an autoinflammatory condition that has helped us understand the mechanisms regulating inflammation
CAPS
Shed light on the role of the NLRP3 inflammasome
What are the symptoms of autoinflammatory syndromes?
Fever
Serositis
Arthritis
Rash
What are common genetic links in autoinflammatory conditions?
Inherited or acquired
Inherited forms usually manifest early
What are the common mechanisms that are faulty in autoinflammatory conditions?
Cytokine dysregulation
Abnormal protostasis
ER and mitochondrial stress
Autophagy
What criteria must a patient follow in order to be diagnosed with an inflammatory condition?
Recurrent or continuous symptoms
Family history
Exclusion of other causes
Elevated acute phase response proteins
What is CAPS?
Range of conditions caused by the same gene mutation
But presents differently
Caused by mutations in the NLRP3 on chromosome 1
What are the three conditions caused by mutations in the NLRP3 gene?
Familial cold urticaria
Muckle Wells Syndrome
NOMID/CINCA
What is the genetic link of Familial cold urticaria?
Autosomal dominant
What is the genetic link of Muckle Wells syndrome?
Autosomal dominant
What is the genetic link of NOMID/ CINCA?
Sporadic
What are the symptoms of Familial Cold Urticaria?
Cold induced rash
Arthralgia
Conjunctivitis
What are the symptoms of Muckle Wells syndrome?
Sensorineural deafness
AA amyloidosis
What are the symptoms of NOMID/CINCA?
Progressive chronic meningitis
Destructive arthritis
What is the severity of Familial cold urticaria?
Mild
Only presents in the cold
What is the severity of Muckle wells syndrome?
Moderate
What is the severity of NOMID/CINCA?
Very severe
Sufferers die in childhood
What are the day-to-day symptoms of CAPS?
Widespread uritcarial rash
Flu-like symptoms
Anaemia
Headaches
Fatigue
Depression
What are the long-term symptoms of CAPS?
Neurological damage
Sensorineural deafness
Visual loss
Cognitive impairment
AA amyloidosis
What activates the NLRP3 inflammasome?
Potassium efflux induced by bacterial proteins or extracellular ATP which interacts with K+ channels
DAMPs or PAMPs forming phagolysosomal vessels
Transcription of proinflammatory cytokines
What type of molecule is NLRP3?
NOD
What are NODs?
As supposed to TLRs, they are cytosolic receptors
Consequences of NLRP3 activation
Amplifies the immune response
Causes apoptosis
How does NLRP3 detect PAMPs or DAMPs?
Through leucine rich repeats
How does the NLRP3 amplify the immune response?
Initiates caspase-1 self-cleavage and forms active caspase-1
How does caspase-1 cause the effects on the inflammatory system?
Stimulates cleavage of pro-IL1b into activated IL-1b
How do mutations to the NLRP3 cause autoinflammatory conditions?
Leads to constitutive overactivation of caspase 1
Leads to spontaneous formation of the IL-1 inflammasome
Continuous production of IL-1b
Which targets does IL-1b affect?
Brain
Bone
Endothelial cells
How does IL-1b affect the brain?
On the hypothalamus
Induces fever and pain sensitisation
How does IL-1b affect bones?
Bone resorption
Cartilage breakdown
Production and enhanced activation of immune cells
Causes the release of inflammatory molecules
How does IL-1b affect endothelial cells?
Releases IL-6
Causes the production and release of acute phase response proteins from the liver
What is the correlation between IL-1b concentration and CAPS presentation?
The higher the IL-1b concentration in the blood, the more severe the presentation of the disease
What are treatments of CAPS?
IL-1 blockade
Caspase 1 inhibition
IL-1b receptor blockade
What was the result of IL-1 blockade as a treatment for CAPS?
Reduced levels of IL-1b
Without decreasing it too much below physiological levels
What was the result of caspase 1 inhibition?
Lowering IL-1b concentration was made possible, but a high amount needed to make a small change
Caspase-1 is important in other processes
Moderately reduced serum cytokine concentration
What is Anakinra?
A drug used for CAPS that blocks the IL-1 receptor
Prevents IL-1b from binding
And so prevents IL-1 from working intracellulary
What is the half-life of Anakinra?
4-6 hours
What was the effect of Anakinra in CAPS patients?
Affected individuals developed normal kidney function and went from infertile to fertile because of the drug
Where is Anakinra derived from?
Recombinant form of endogenous IL-1Ra
What were the limitations of Anakinra?
Difficult to obtain funding for the expensive drug
Daily sometimes painful injections required
Injection site reactions
Inconvenient - needs to be stored between 2-8 degrees, repeated dosing within 24 hr is crucial
Major rebound flares
Infectious risks
What are the advantages of Anakinra?
Short half-life meant it was safe since it was cleared out in the urine within a few hours
CAPS sufferers were sensitive to IL-1 receptor blockade when all other therapies were unsuccessful
Why was CAPS a good disease to test novel therapies?
IL-1 was thought to play a major role in many acquired diseases
CAPS is a disease with very clear parameters
Why is CAPS a condition with clear parameters?
Patients have defined, clear symptoms
There is a genetic test for the condition
Blood test results correlated with the level of disease in the patient
What was found to be a good alternative drug to Anakinra?
Canakinumab
Why was Canakinumab a better alternative than Anakinra?
Fully human IgG cap antibody targeted against IL-1b
Showed rapid improvement of symptoms within hours
Levels of biomarkers lowered to normal and maintained for 115 days after one dose
What is the safety profile of Canakinumab?
Well-tolerated
Few infection-site reactions
No evidence for development of antibodies or immunogenicity
What conditions are similar to CAPS?
Familial Mediterranean Fever
TRAPS
DIRA
DITRA
MKD
What is FMF?
Familial Mediterranean Fever
Commonest genetic disease in the East Mediterranean
What are the symptoms of FMF?
Recurrent, self-limiting episodes of fever, peritonitic pain, pleurtic pain and arthritis
Lasts 48-72 hours
What gene defect leads to FMF?
Mutation in the MEFV gene
How does the mutation of MEFV lead to FMF?
MEFV gene codes for the pyrin protein
This is a gain of function mutation
Causes overactivation of caspase-1 and more IL-1b to become released
Do FMF patients have increased or decreased chances of developing infections?
Decreased
These patients have lower infection rates because of the increased IL-1b release
What is pyrin?
A component of the inflammasome
What is the function of pyrin?
Activates caspase-1 by autoproteolysis
Indirect sensor of many bacterial toxins through their effects on actin
What is colchicine?
An effective prophylaxis to FMF
Root found naturally
Why is colchicine effective in FMF if it has a low therapeutic index?
It concentrates in neutrophils
Because they lack the P-glycoprotein efflux pump that removes it from the inside of the cell
How does colchicine effectively treat FMF?
Competes with cleaving of NF-kB
Decreases the concentration of NFkB in the blood
How does colchicine cause effects on the cells it targets?
Binds to tubulin to arrest microtubule polymerization
Inhibits neutrophil chemotxis
Suppresses NF-kB activation
Reduces levels of inflammatory cytokines
What is the mortality of FMF patients?
Comparable to normal population
AA amyloidosis causes death in the undiagnosed population
What are the reproductive outcomes of FMF patients?
Comparable to the normal population
Colchicine does not have effects on fertility
What are the incidences of colchicine resistance in FMF patients?
Rare
IL-1 agents are used in such case
